The present invention pertains in large part to cancer treatment, targeted therapies, tyrosine kinase inhibitors, certain chemical compounds, chemical syntheses, compositions, and methods of treating, e.g., tumors and other cancers with the compounds, including conditions in which FAK plays a significant role or FAK inhibition can be beneficial.
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase which plays a major role in the transduction of the signal transmitted by integrins, a family of heterodimeric receptors for cell adhesion. FAK and integrins are colocalized in perimembrane structures called adhesion plaques.
FAK signaling through ERK, PI3K, and p130cas is important in cancer cell proliferation, survival, and migration. pFAK and/or FAK overexpression has been reported in many cancer tumors. An increase in the proliferation of tumor cells in vivo has been observed after induction of the expression of FAK in human astrocytoma cells. Cary et al., J. Cell Sci., 109:1787-94 (1996). FAK is overexpressed in prostate, breast, thyroid, colon, melanoma, brain and lung cancers, the level of FAK expression being directly correlated with tumors exhibiting the most aggressive phenotype. Weiner et al., Lancet, 342(8878):1024-25 (1993); Owens et al., Cancer Res., 55:2752-55 (1995); Maung et al., Oncogene, 18:6824-28 (1999); Wang et al., J. Cell Sci., 113:4221-30 (2000). FAK is highly active in human epithelial and mesenchymal tumors such as melanoma, lymphoma, and multiple myeloma. Increased FAK correlates with increased invasiveness and increased ability of cancer to metastasize.
Inhibition of FAK signaling in vitro induces cell growth arrest, reduces motility, and can cause cell death. KD-FAK and DN-FAK have been shown to inhibit tumor growth in vivo. FAK is also known as PTK2.
In hepatocytes, TGFβ induces a Src-dependent activation of FAK; and there is evidence that FAK signaling is required for transcriptional up-regulation of mesenchymal and invasiveness markers and for delocalization of membrane-bound E-cadherin. Exp. Cell Res., 314, 143-52 (2008).
A number of publications and documents disclose compounds said to possess FAK or other kinase inhibiting activity, e.g., Cancer Res., 68(6), 1935-1944 (2008), U.S. application Ser. No. 12/791,047 (Jun. 1, 2010), U.S. Pat. No. 6,649,608, U.S. Pat. No. 6,878,697, U.S. Pat. No. 7,109,335, U.S. Pat. No. 7,109,337, U.S. Pat. No. 7,122,670, U.S. Pat. No. 7,230,098, U.S. Pat. No. 7,351,712, U.S. Pat. No. 7,514,446, U.S. Pat. No. 7,521,457, US2004/0220177, US2005/0124637, US2005/0203114, US2005/0256144, US2005/0256145, US2006/0252748, US2007/0015207, US2007/0203161, US2008/0039447, US2008/0132504, US2008/0176881, US2008/0182840, US2008/0293708, US2009/0054395, US2009/0149438, US2009/0286778; WO2001/64655, WO2001/070741, WO02/096888, WO2006/021544, WO2007/021937, WO2008/051547, WO2008/094602, WO2008/094737, WO2008/129380, WO2009/020990, WO2009/071535, WO2009/105498, WO2009/143389, WO2010/028116.
There remains a need for new kinase inhibitors, including FAK inhibitors, having the potential to reach the clinic and regulatory approval for treating disease such as cancer, among others.